Key Points
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Strong cytotoxic T lymphocyte (CTL) responses to cellular antigen that does not provide its own endogenous inflammatory signals require CD4+ T cells to recognize antigen.
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The role of CD4+ T cells is to activate or 'license' the ability of dendritic cells (DCs) to present antigen, so that a strong CD8+ T-cell response can ensue.
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When antigen is in the form of a pathogen, the need for CD4+ T-cell recognition of antigen may be overridden, as the DC can be activated directly by pathogen-associated molecular patterns.
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When CD8+ T-cell responses are induced in a CD4+ T-cell-deficient environment, even though a good primary response occurs, the ability to make a good secondary response fades.
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This finding has been interpreted either as a requirement for CD4+ T cells to programme CD8+ T cells for long-term memory differentiation, or for CD4+ T cells to provide factors that maintain CD8+ memory T cells.
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When antigen persists in an animal, memory CD8+ T-cell differentiation cannot occur. Depending on the level of persistent antigen, the CD8+ T cells might be rapidly or slowly eliminated. Whether CD4+ T cells can directly promote CD8+ T-cell survival in the presence of persisting antigen is unclear.
Abstract
Cytotoxic T lymphocytes (CTLs) that express the CD8 co-receptor are the guided missiles of the immune system. They express clonally distributed receptors for foreign antigen, undergo marked proliferation in response to infection and kill any cell that expresses their target antigen. When an infection is cleared or brought under control, the progeny of these cytolytic effectors are retained as an essential component of immunological memory. As I discuss here, similar to other aspects of immunity, their clonal expansion and survival depend on the activity of CD4+ T cells, although the mechanism(s) of 'help' for CTL responses is still debated.
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Glossary
- MIXED LYMPHOCYTE REACTION
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A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.
- HISTOCOMPATIBILITY ANTIGEN H-Y
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H-Y is a protein encoded on the Y chromosome. Female T cells respond to peptides derived from this protein and so H-Y is a male-specific histocompatibility antigen. Furthermore, T-cell receptors (TCRs) specific for this antigen have been cloned and used to generate distinct lines of TCR-transgenic mice.
- IN VITRO RESTIMULATION
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Some cytotoxic T lymphocyte responses are too weak to be measured directly ex vivo. In this case, spleen or blood cells can be stimulated for 5 days in culture with antigen to increase the number of antigen-specific CD8+ T cells.
- T-CELL–B-CELL COOPERATION
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For B cells to make high-affinity antibodies and switch from IgM to other immunoglobulin subclasses they require help from CD4+ T cells. Activated CD4+ T cells recognize endocytosed antigen presented by MHC class II molecules on the B cell and stimulate the B cell through CD40–CD40 ligand interactions.
- PRIMARY RESPONSE
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The response to initial immunization. In the case of CD8+ T-cell responses, this is usually measured at day 7–8 after immunization.
- SECONDARY RESPONSE
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When the first encounter with antigen has been cleared, a response to subsequent immunization with the same antigen is referred to as a secondary or recall response.
- TETRAMER STAINING
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Biotinylated monomeric MHC molecules are folded in vitro with a specific peptide in the binding groove and tetramerized with a fluorescently labelled streptavidin molecule. Tetramers will bind to T cells that express T-cell receptors specific for the cognate peptide–MHC complex and can therefore be used to track antigen-specific T cells by flow cytometry.
- ELISPOT
-
An antibody-capture-based method for enumerating specific T cells (CD4+ and CD8+) that can secrete cytokines (usually interferon-γ).
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Bevan, M. Helping the CD8+ T-cell response. Nat Rev Immunol 4, 595–602 (2004). https://doi.org/10.1038/nri1413
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DOI: https://doi.org/10.1038/nri1413
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